The integrity of the blood-brain barrier (BBB) is critical for normal brain function. Neuropathological disorders in AIDS patients have been associated with perivascular HIV-infected macrophages, gliosis and abnormalities in the permeability of the BBB. Breakdown of the BBB is commonly seen in AIDS patients with HIV-1 associated dementia (HAD). The processes by which HIV causes these pathological changes are not well understood. This proposal seeks to characterize the role of brain endothelium in contributing to HIV-1 related neurological pathology. Gp120, the HIV-1 envelope glycoprotein, has been detected in the serum and cerebrospinal fluid of HIV-1 infected patients at 0.1 nM to 1 nM concentrations and can act as a soluble mediator. Gp120 protein can elicit neurotoxic substances and is detected in the brains of patients with AIDS. The overall hypotheses of this proposal are: 1) Gp120 may interact with brain endothelium and cause cell injury, thereby facilitating transit of HIV into the CNS as well as contributing to the pathology in brain;2) brain endothelium may serve as a microenvironment which promotes HIV-1 infection in brain via the binding of Gp120 to the syndecans on the surface of brain endothelium;and 3) opioid drugs may hasten the progression of HAD due to a synergistic toxic effect of Gp120 and opioids on brain endothelium. This proposal will characterize the pathogenic effects of Gp120 on human brain microvascular endothelial cells (HBMEC), at concentrations of the viral envelope Gp120 that are found in vivo (0.1 to 1 nM). The aims of this research are: 1) to characterize the molecular mechanisms of Gp120 mediated injury of brain endothelium by elucidating the signaling pathways that mediate the injurious effects of Gp120 in HBMEC as compared to human umbilical vein endothelial cells (HUVEC) in-vitro and in-vivo;2) to determine the role of syndecans as attachment receptors for Gp120 on endothelial cells and their role in HIV-mediated brain endothelium injury;and 3) to examine the potential synergistic toxicity of Gp120 and opioid drugs (morphine) on HBMEC permeability. In these studies, we will work with both M- and T-tropic HIV strains, since each can be present during the course of AIDS. These studies should provide insights into preventive and/or therapeutic strategies to sustain BBB integrity in HIV-infected patients, and thereby contribute to limiting CNS pathology.